Hierarchy within the mammary STAT5-driven Wap super-enhancer
- Authors
- Shin, Ha Youn; Willi, Michaela; Yoo, Kyung Hyun; Zeng, Xianke; Wang, Chaochen; Metser, Gil; Hennighausen, Lothar
- Issue Date
- Aug-2016
- Publisher
- NATURE PUBLISHING GROUP
- Citation
- NATURE GENETICS, v.48, no.8, pp 904 - 911
- Pages
- 8
- Journal Title
- NATURE GENETICS
- Volume
- 48
- Number
- 8
- Start Page
- 904
- End Page
- 911
- URI
- https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/3300
- DOI
- 10.1038/ng.3606
- ISSN
- 1061-4036
1546-1718
- Abstract
- Super-enhancers comprise dense transcription factor platforms highly enriched for active chromatin marks. A paucity of functional data led us to investigate the role of super-enhancers in the mammary gland, an organ characterized by exceptional gene regulatory dynamics during pregnancy. ChIP-seq analysis for the master regulator STAT5A, the glucocorticoid receptor, H3K27ac and MED1 identified 440 mammary-specific super-enhancers, half of which were associated with genes activated during pregnancy. We interrogated the Wap super-enhancer, generating mice carrying mutations in STAT5-binding sites within its constituent enhancers. Individually, the most distal site displayed the greatest enhancer activity. However, combinatorial mutation analysis showed that the 1,000-fold induction in gene expression during pregnancy relied on all enhancers. Disabling the binding sites of STAT5, NFIB and ELF5 in the proximal enhancer incapacitated the entire super-enhancer. Altogether, these data suggest a temporal and functional enhancer hierarchy. The identification of mammary-specific super-enhancers and the mechanistic exploration of the Wap locus provide insights into the regulation of cell-type-specific expression of hormone-sensing genes.
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